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EP1817026A2 - Inhibiteurs du virus de l'hepatite c - Google Patents

Inhibiteurs du virus de l'hepatite c

Info

Publication number
EP1817026A2
EP1817026A2 EP05857834A EP05857834A EP1817026A2 EP 1817026 A2 EP1817026 A2 EP 1817026A2 EP 05857834 A EP05857834 A EP 05857834A EP 05857834 A EP05857834 A EP 05857834A EP 1817026 A2 EP1817026 A2 EP 1817026A2
Authority
EP
European Patent Office
Prior art keywords
carbazol
optionally substituted
bromo
tetrahydro
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05857834A
Other languages
German (de)
English (en)
Inventor
Kristjan GlaxoSmithKline GUDMUNDSSON
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1817026A2 publication Critical patent/EP1817026A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to compounds useful as anti-viral agents.
  • the present invention relates to compounds that are useful in the treatment of viruses belonging to Flaviviridae, including flaviviruses, pestiviruses, and hepaciviruses.
  • the invention includes compounds useful for the treatment or prophylaxis of dengue fever, yellow fever, West Nile virus, and HCV.
  • HCV infection is responsible for 40- 60% of all chronic liver disease and 30% of all liver transplants.
  • Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.
  • Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection.
  • adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K. L. (1997) Hepatology 26 (suppl 1): 71S-77S).
  • HCV hepatitis C virus
  • NANBH non-B hepatitis
  • HCV bovine viral diarrhea virus, border disease virus, and classic swine fever virus
  • the HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA- A Publication of the RNA Society. 1(5): 526-537, 1995 JuI.). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • ORF long open reading frame
  • this RNA Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of ⁇ 3000 amino acids comprising both the structural and nonstructural viral proteins.
  • This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2 nd Edition, p931-960; Raven Press, N.Y.).
  • 3 1 NTR which roughly consists of three regions: an ⁇ 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3' X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371 ; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215:744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261).
  • the 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.
  • the present invention includes a method for the treatment or prophylaxis of Flaviviridae viruses through administration of a compound of formula (I):
  • n 0,1 , or 2; R is hydrogen or alkyl; X is NR 2 , O, or S(O) m ; each R 1 is the same or different and is independently selected from the group consisting of hydrogen, halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R 10 cycloalkyl, Ay, -NHR 10 Ay, Het, -NHHet, -NHR 10 Het, -OR 2 , -OAy, - OHet, -R 10 OR 2 , -NR 2 R 3 , -NR 2 Ay, -R 10 NR 2 R 3 , -R 10 NR 2 Ay, -R 10 C(O)R 2 , -C(O)R 2 , - CO 2 R 2 , -R 10 CO 2 R 2 , -R 10 CO 2 R 2 , -C(O)
  • Z is -R 2 , -OR 2 , -C(O)R 2 , -C(O) 2 R 2 , -S(O) m R 2 , -C(O)NR 2 R 3 , -Het, or -Ay, provided when d is O, then Z is not -Het or -Ay; each m independently is O, 1 or 2; each R 10 is the same or different and is independently selected from alkylene, cycloalkylene, alkenylene, cycloalkenylene, and alkynylene; p is selected from 0, 1 , 2, 3, or 4; each of R 2 and R 3 are the same or different and are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, -R 10 cycloalkyl, -R 10 OH, -R 10 (OR 10 ) W , and -R 10 NR 5 R 6
  • Ay represents an optionally substituted aryl group
  • Het represents an optionally substituted 5- or 6-membered heterocyclyl or heteroaryl group; including administration of pharmaceutically acceptable salts, solvates, and physiologically functional derivatives thereof.
  • the Flaviviridae virus is a flavivirus, a pestivirus, or a hepacivirus. More particularly, the virus is associated with a human disease selected from dengue fever, yellow fever, west nile virus, and HCV. Further, preferably the method is for the treatment or prophylaxis of HCV infection.
  • Y is optionally substituted alkylene, namely optionally substituted with alkyl, dialkyl, or aryl. More preferably Y is methylene substituted with methyl, dimethyl, or optionally substituted phenyl.
  • Y is optionally substituted cycloalkylene. More preferably Y is indane.
  • Ay is a substituted aryl
  • said aryl is substituted with alkyl, alkoxy, halogen, haloalkyl, alkylamine, nitro, or cyano.
  • R 1 is halogen. More preferably R 1 is bromo or chloro.
  • n 1
  • X is -NH.
  • Z is -Ay. More preferably -Ay is phenyl.
  • p is 1
  • R 1 is halogen
  • n is 1
  • X is NH
  • (Y) d is substituted alkylene
  • Z is aryl. More preferably R 1 is bromo or chloro and is substituted para to the depicted N atom, said alkylene is substituted with alkyl, and said aryl is phenyl. More preferably alkyl is methyl.
  • p is 1
  • R 1 is halogen
  • n is 1
  • X is NH
  • (Y) d is cycloalkylene
  • Z is R 2 . More preferably R 1 is bromo or chloro and is substituted para to the depicted N atom, R 2 is hydrogen, and (Y) d is indane.
  • the present invention includes the use of a compound of formula (I): wherein the variables are as defined in the manufacture of a medicament for use in the treatment or prophylaxis of viruses belonging to Flaviviridae.
  • the virus is a flavivirus, a pestivirus, or a hepacivirus.
  • the disease or condition is dengue fever, yellow fever, west nile virus, or HCV.
  • the condition or disorder is HCV.
  • p and q are each independently defined as 0, 1 , 2, 3, 4, or 5.
  • the value(s) of p and/or q should not exceed the substitutable positions on the depicted rings.
  • alkyl refers to a straight or branched chain hydrocarbon, preferably having from one to twelve carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, isopentyl, n-pentyl, and the like.
  • C x- C y alkyl refers to an alkyl group, as herein defined, containing the specified number of carbon atoms. Similar terminology will apply for other preferred terms and ranges as well.
  • alkenyl refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon double bonds. Examples include, but are not limited to, vinyl, allyl, and the like.
  • alkynyl refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon triple bonds. Examples include, but are not limited to, ethynyl and the like.
  • alkylene refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms. Alkylene groups as defined herein may optionally be substituted. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, n- propylene, n-butylene. As used herein, the term “alkenylene” refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms, containing one or more carbon-to-carbon double bonds that may be optionally substituted. Examples include, but are not limited to, vinylene, allylene or 2- propenylene, and the like.
  • alkynylene refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms, containing one or more carbon-to-carbon triple bonds that may be optionally substituted. Examples include, but are not limited to, ethynylene and the like.
  • cycloalkyl refers to an optionally substituted non- aromatic cyclic hydrocarbon ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached.
  • exemplary "cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and substituted versions thereof.
  • cycloalkyl includes an optionally substituted fused polycyclic hydrocarbon saturated ring and aromatic ring system, namely polycyclic hydrocarbons with less than maximum number of non- cumulative double bonds, for example where a saturated hydrocarbon ring (such as a cyclopentyl ring) is fused with an aromatic ring (herein “aryl,” such as a benzene ring) to form, for example, groups such as indane.
  • aryl such as a benzene ring
  • cycloalkenyl refers to an optionally substituted non- aromatic cyclic hydrocarbon ring containing one or more carbon-to-carbon double bonds which optionally includes an alkylene linker through which the cycloalkenyl may be attached.
  • exemplary "cycloalkenyl” groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and substituted versions thereof.
  • cycloalkylene refers to a divalent, optionally substituted non-aromatic cyclic hydrocarbon ring.
  • exemplary "cycloalkylene” groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like.
  • cycloalkenylene refers to a divalent optionally substituted non-aromatic cyclic hydrocarbon ring containing one or more carbon-to- carbon double bonds.
  • exemplary "cycloalkenylene” groups include, but are not limited to, cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, cycloheptenylene, and the like.
  • heterocycle or “heterocyclyl” refers to an optionally substituted mono- or polycyclic ring system containing one or more degrees of unsaturation and also containing one or more heteroatoms.
  • heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to twelve-membered and is either fully saturated or has one or more degrees of unsaturation.
  • Such rings may be optionally fused to one or more of another "heterocyclic" ring(s) or cycloalkyl ring(s).
  • heterocyclic groups include, but are not limited to, tetrahydrofuran, pyran, 1 ,4-dioxane, 1 ,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene.
  • aryl refers to an optionally substituted benzene ring or to an optionally substituted fused benzene ring system, for example anthracene, phenanthrene, or naphthalene ring systems.
  • aryl groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, and the like.
  • heteroaryl refers to an optionally substituted monocyclic five to seven membered aromatic ring, or to an optionally substituted fused bicyclic aromatic ring system comprising two of such aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen atoms, where N- oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • heteroaryl groups used herein include, but should not be limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, benzimidizolyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, and the like.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group, as defined herein, that is substituted with at least one halogen.
  • branched or straight chained “haloalkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo, and iodo.
  • haloalkyl should be interpreted to include such substituents as perfluoroalkyl groups and the like.
  • alkoxy refers to the group -OR a , where R a is alkyl as defined above.
  • alkoxycarbonyl refers to groups such as: where the R a represents an alkyl group as herein defined.
  • aryloxycarbonyl refers to groups such as:
  • Ay represents an aryl group as herein defined.
  • heteroaryloxycarbonyl refers to groups such as:
  • Het represents a heteroaryl group as herein defined.
  • nitro refers to the group -NO 2 .
  • cyano refers to the group -CN.
  • azido refers to the group -N 3 .
  • acyl refers to the group R b C(0)-, where R b is alkyl, aryl, heteroaryl, or heterocyclyl, as each is defined herein.
  • Exemplary optional substituent groups include acyl; alkyl; alkenyl; alkynyl; alkylsulfonyl; alkoxy; alkoxycarbonyl; cyano; halogen; haloalkyl; hydroxy; nitro; aryl, which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro; heteroaryl, which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro; arylsulfonyl, which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano,
  • the compounds of formulas (I) may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms (“polymorphs") are within the scope of formula (I).
  • Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers.
  • the scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I), as well as any wholly or partially equilibrated mixtures thereof.
  • the present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts.
  • Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula I, or a salt or physiologically functional derivative thereof) and a solvent.
  • solvents for the purpose of the invention, should not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Most preferably the solvent used is water.
  • physiologically functional derivative refers to any pharmaceutically acceptable derivative of a compound of the present invention that, upon administration to a mammal, is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof.
  • Such derivatives for example, esters and amides, will be clear to those skilled in the art, without undue experimentation.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • therapeutically effective amounts of a compound of formula (I), as well as salts, solvates, and physiological functional derivatives thereof may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
  • the invention further provides pharmaceutical compositions that include effective amounts of compounds of the formula (I) and salts, solvates, and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof, are as herein described.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I) or salts, solvates, and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors. For example, the species, age, and weight of the recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant physician or veterinarian. Regardless, an effective amount of a compound of formula (I) for the treatment of humans suffering from frailty, generally, should be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day. More usually the effective amount should be in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal the actual amount per day would usually be from 70 to 700 mg.
  • This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt, solvate, or physiologically functional derivative thereof, may be determined as a proportion of the effective amount of the compound of formula (I) per se. Similar dosages should be appropriate for treatment of the other conditions referred to herein.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, as a non-limiting example, 0.5mg to 1g of a compound of the formula (I), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by an oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • the carrier(s) or excipient(s) By way of example, and not meant to limit the invention, with regard to certain conditions and disorders for which the compounds of the present invention are believed useful certain routes will be preferable to others.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each with aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • powders are prepared by comminuting the compound to a suitable fine size and mixing with an appropriate pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavorings, preservatives, dispersing agents, and coloring agents can also be present.
  • Capsules are made by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or some other appropriate shell material.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the mixture before the encapsulation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • binders examples include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants useful in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture may be prepared by mixing the compound, suitably comminuted, with a diluent or base as described above.
  • Optional ingredients include binders such as carboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone, solution retardants such as paraffin, resorption accelerators such as a quaternary salt, and/or absorption agents such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be wet-granulated with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials, and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet-forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated generally by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives; flavor additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners; and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of formula (I) and salts, solvates, and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • the compounds of formula (I) and salts, solvates, and physiologically functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl- aspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug; for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986), incorporated herein by reference as related to such delivery systems.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • the formulations may be applied as a topical ointment or cream.
  • the active ingredient When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes.
  • compositions adapted for nasal administration where the carrier is a solid, include a coarse powder having a particle size for example in the range 20 to 500 microns.
  • the powder is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, or insufflators.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question.
  • formulations suitable for oral administration may include flavoring or coloring agents.
  • the compounds of the present invention and their salts, solvates, and physiologically functional derivatives thereof may be employed alone or in combination with other therapeutic agents.
  • the compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of formula (I) salts, solvates, or physiologically functional derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions. Treatment will depend upon the nature and type of viral infection.
  • the present invention may be combined with other medical therapies including a variety of cytotoxic or antiviral agents.
  • the compounds of the present invention may be combined with other therapeutic agents for example immune therapies (such as interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents (such as corticosteroids or NSAIDs), bronchodilators such as beta-2 adrenergic agonists and xanthines (such as theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (such as ICAM antagonists), anti-oxidants (such as N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (such as ribavirin and amantidine).
  • immune therapies such as interferon
  • therapeutic vaccines such as antifibrotic agents, anti-inflammatory agents (such as corticosteroids or NSAIDs), bronchodilators such as beta-2 adrenergic agonists and xanthines (such as theophy
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • the compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (I).
  • the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- Interscience, 1994), incorporated by reference with regard to stereochemistry.
  • RT room temperature
  • h hours
  • min minutes
  • TLC thin layer chromatography
  • mp melting point
  • RP reverse phase
  • Tr retention time
  • TFA trifluoroacetic acid
  • TEA triethylamine
  • THF tetrahydrofuran
  • TFAA trifluoroacetic anhydride
  • CD3OD deuterated methanol
  • CDCI3 deuterated chloroform
  • DMSO dimethylsulfoxide
  • SiO2 (silica); atm (atmosphere);
  • Mass spectra were obtained on Micromass Platform or ZMD mass spectrometers from Micromass Ltd., Altricham, UK, using either Atmospheric Chemical Ionization (APCI) or Electrospray Ionization (ESI).
  • APCI Atmospheric Chemical Ionization
  • ESI Electrospray Ionization
  • the absolute configuration of compounds were assigned by Ab lnitio Vibrational Circular Dichroism (VCD) Spectroscopy.
  • the experimental VCD spectrum were acquired in CDCI 3 using a Bomem ChirallRTM VCD spectrometer operating between 2000 and 800 cm "1 .
  • the Gaussian 98 Suite of computational programs was used to calculate model VCD spectrums.
  • the stereochemical assignments were made by comparing this experimental spectrum to the VCD spectrum calculated for a model structure with (R)- or (S)-configuration.
  • Incorporated by reference with regard to such spectroscopy are: J.R. Chesseman, MJ. Frisch, FJ. Devlin and PJ. Stephens, Chem. Phys. Lett. 252 (1996) 211; PJ. Stephens and FJ. Devlin, Chirality 12 (2000) 172; and Gaussian 98, Revision A.11.4, MJ. Frisch et al., Gaussian, Inc., Pittsburgh PA, 2002.
  • the process for preparing the compounds of formula (I), where LV is as defined above comprises the steps of: a) reacting a compound of formula (II) with ethyl formate; b) reacting the compound of formula (III) with diazocompound of formula (IV);
  • the reaction may be carried out as a two step process where an imine is formed under conditions that allow for removal of water followed by reduction.
  • this reaction can be carried out in one pot by adding amine (VIII) and the reductive agent, either sequentially or at the same time.
  • a compound of formula (Vl) is dissolved in an inert solvent such as toluene, and either an equivalent or an excess of an amine of formula (VIII) is added, followed by the optional addition of an acid catalyst such as para-toluenesulfonic acid.
  • an acid catalyst such as para-toluenesulfonic acid.
  • the reaction is heated to reflux for azeotropic removal of water.
  • molecular sieves or dehydrating agents such as trimethylorthoformate, can be used for the removal of water.
  • the imine can be isolated or used directly for the next step.
  • the imine is dissolved in a suitable solvent and reduced by additon of a reductive agent.
  • suitable solvents include lower alcohols (methanol, ethanol, and the like) tetrahydrofuran, or other similar solvents well known to those skilled in the art.
  • Suitable reductive agents include, but are not limited to, sodium cyanoborohydride, sodium triacetoxyborohydride, borane-tetrahydrofuran complex, sodium borohydride, and the like.
  • a compound of formula (Vl) is dissolved in an inert solvent.
  • An amine of formula (VIII) is added to this solution, followed by the addition of a suitable reductive agent.
  • the reaction may optionally be heated to between about 50°C-150 0 C.
  • suitable solvents include but are not limited to, dichloromethane, dichloroethane, and the like.
  • Suitable reductive agents include but are not limited to sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, and the like.
  • a compound of formula (I) can be formed from an amine of formula (VII).
  • Suitable solvents include, but are not limited to, methanol, ethanol, dichloro-methane, dichloroethane, and the like.
  • Suitable reductive agents include, but are not limited to, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, and the like.
  • Suitable ammonium salts include, but are not limited to, ammonium acetate, ammonium formate, and the like.
  • An amine of formula (VII) can also be formed by treatment of compound of formula (Vl) with hydroxylamine, followed by reduction with suitable reductive agents which include, but are not limited to, lithium aluminium hydride and the like.
  • Condensation of compound of formula (VII) with compound of formula (IX) gives compound of formula (I).
  • This condensation can be carried out neat or in the presence of solvent, optionally with heating.
  • the condensation optionally may be carried out in a microwave.
  • Suitable solvents include, but are not limited to, N 1 N- dimethylformamide, 1-methyl-2-pyrrolidinone, dimethyl-sulfoxide, acetonitrile, nitromethane and the like.
  • a base may be added to the condensation reaction. Examples of suitable bases include, but are not limited to, sodium carbonate, sodium bicarbonate, triethylamine, and the like.
  • a compound of formula (VII) can be treated with isocyanate in a suitable solvent, optionally with heating.
  • suitable solvents include, but are not limited to, tetrahydrofuran, dichloromethane, lower alcohols (methanol, ethanol), and the like.
  • Isocyanates are commercially available and/or can be made by methods readily available or known to those skilled in the art.
  • the process for preparing the compounds of formula (I), where X is O and -((Y) d — Z) is as defined above comprises the steps of: a) forming a compound illustrated by formula (X) by protecting the depicted nitrogen in a compound of formula (Vl); b) reducing compound of formula (X) to an alcohol of formula (Xl); c) reaction of compound of formula (Xl) with a compound of formula (XII) to give compound of formula (XIII); d) deprotection of compound of formula (XIII) to give a compound of formula (I) where X is O and -((Y) d — Z) is as herein defined;
  • Scheme 3 illustrates one embodiment of this general process using a preferred protecting group, namely benzene sulfonylchloride. More specifically the depicted indole nitrogen in a compound of formula (Vl) is protected using a suitable protecting group.
  • Suitable protecting groups include phenylsulfonyl and other related protecting groups.
  • Suitable reducing agents include, but are not limited to, sodium borohydride, diborane, and the like.
  • Suitable solvents for the reduction include, but are not limited to, tetrahydrofuran, halogenated solvents (dichloromethane and the like), lower alcohols (methanol, ethanol, and the like), and other similar solvents.
  • Suitable solvents include, but are not limited to, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, nitromethane, tetrahydrofuran, and the like.
  • Suitable bases include, but are not limited to, sodium hydride, sodium f-butoxide, and the like.
  • a compound of formula (I) where X is N and -((Y)d — Z) is substituted alkylene— Ay can be prepared from a compound of formula (VII).
  • More specifically compound of formula (VII) can be reduced to an alcohol of formula (XIV) with a suitable reducing agent.
  • suitable reducing agents include, but are not limited to, sodium borohydride, diborane, and the like.
  • Suitable solvents for the reduction include, but are not limited to, tetrahydrofuran, dichloromethane, and lower alcohols (methanol, ethanol, and the like).
  • An alcohol of formula (XIV) can be treated with an amine of formula (XV) at high temperature, optionally in the presence of acid catalyst to give a compound of formula (I) where -((Y) d — Z) is substituted alkylene— Ay, such as -CR * R ** Ay.
  • R* and R** may be a variety of substituents, including the substituents listed herein under the description of optionally substituted.
  • one of R* and R** is H and the other is selected from H, alkyl, or aryl; or both R* and R * * are alkyl.
  • This reaction may be performed in a microwave, as described below in more detail.
  • the process for preparing compound of formula (I) where a halogen (HaI) is at the 8-position comprises the steps of: a) reaction of a compound of formula (XV) with 3-bromocyclohexene to give a compound of formula (XVI); b) rearrangement of a compound of formula (XVI) to give a compound of formula (XVII); c) cyclization of a compound of formula (XVII) to give a compound of formula (XVIII); d) reaction of a compound of formula (XVIII) with an amine (e.g., Z-(Y)d-NH 2 ) to form a compound of formula (XIX); and e) oxidation of a compound of formula (XIX) to give a compound of formula (I).
  • Suitable solvents include, but are not limited to, N,N-dimethylformamide, acetonitrile, nitromethane, and the like.
  • Suitable bases include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, and the like.
  • Suitable solvents include high boiling solvents, such as xylene and the like.
  • Suitable Lewis acids include, but are not limited to, zinc chloride and the like.
  • Suitable bases include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, and the like.
  • Suitable solvents include, but are not limited to, tetrahydrofuran, acetonitrile, dichloromethane, and the like.
  • Reaction of a compound (XVIII) with an amine of formula Z-(Y) d -NH 2 in a suitable solvent, optionally with heating and optionally in the presence of base gives a compound of formula (XIX).
  • a suitable solvent include, but are not limited to, N,N-dimethylformamide, nitromethane, acetonitrile, and the like.
  • Suitable bases include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, and the like.
  • the reaction can optionally be heated to between about 30-200 0 C or carried out in a microwave.
  • a compound of formula (XIX) then is oxidized to give compound of formula (I).
  • Suitable oxidizing agents include, as depicted, but should not be considered limiting, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone ("DDQ") and the like.
  • Suitable solvents for the reaction include halogenated solvents (such as dichloromethane). The reaction can be carried out at room temperature or optionally with heating.
  • Example 1 6-Chloro-2,3,4,9-tetrahvdro-1 /-/-carbazol-1 -one.
  • 6-Bromo-2,3,4,9-tetrahydro-1H-carbazol ⁇ 1-one was prepared from bromoaniline and 2-(hydroxymethyIene)cyciohexanone in a similar manner as described above to give a brown solid.
  • 6-Methyl-2,3,4,9-tetrahydro-1/-/-carbazol-1-one was prepared from p-toluidine and 2- (hydroxymethylene)cyclohexanone in a similar manner as described above to give a tan solid.
  • 6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1 -amine was prepared in a similar manner as described above to give a solid.
  • the oxime was dissolved in THF (80 mL) and lithium aluminium hydride (1.0 M in THF, 24.3 mL) was added dropwise. The reaction was heated at reflux for 7 h and cooled in an ice bath. Methanol was added dropwise until bubbling ceased. The mixture was diluted with aqueous Na/K tartrate, stirred vigorously for 15 min and extracted with ethyl acetate (2 x 100 mL). The extracts were combined, dried over sodium sulfate, filtered, and concentrated.
  • the crude amine was purified by flash chromatography on silica (2% to 5% methanol/methylene chloride gradient) to provide 2,3,4, 9-tetrahydro-1H-carbazol-1 -amine as a brown oil.
  • the oil was diluted in diethyl ether and HCI (1.0 M in diethyl ether) was added. The resulting precipitate was collected by filtration to provide 2,3,4,9-tetrahydro-1H-carbazol-1 -amine hydrochloride (760 mg, 42%). as a light brown solid.
  • 6-Methoxy-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared from p-anisidine and 2-(hydroxymethylene)cyclohexanone in a similar manner as described above to give a tan solid.
  • Example 10 6-Methoxy-2,3,4,9-tetrahydro-1H-carbazol-1 -amine
  • 6-(Trifluoromethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared from 4- (trifluoromethyl)aniline (5.5 g, 34 mmol) and 2-(hydroxymethylene)cyclohexanone (3.9 g, 31 mmol) in a similar manner as described above to give 2.25 g (29%). of a dark brown solid.
  • the oxime was dissolved in THF (54 mL) and LAH (1.0 M in THF, 16.2 mL, 16.2 mmol) was added dropwise. The reaction was heated at reflux for 4 h and cooled in an ice bath. Methanol was added dropwise until bubbling ceased. The mixture was diluted with aqueous NaHSO 3 and stirred vigorously for 15 min and extracted with ethyl acetate (2 x 150 mL). The extracts were combined, dried over sodium sulfate, filtered and concentrated.
  • the crude amine was purified by flash chromatography on silica (2% to 5% methanol/methylene chloride gradient) to provide 2-bromo-5,5a,6 ) 7,8,9,10,10a- octahydrocyclohepta[ ⁇ b]indol-6-amine as a brown oil.
  • the oil was diluted in diethyl ether and HCI (1.0 M in diethyl ether) was added.
  • the resulting precipitate was collected by filtration to provide 2-bromo-5,5a,6,7,8,9,10,10a- octahydrocyclohepta[ ⁇ ]indol-6-amine hydrochloride (980 mg, 57%). as a light brown solid.
  • ⁇ /-(4-Methoxybenzyl)-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 2,3,4, 9-tetrahydro-1 H-carbazol-1 -one (0.1 g, 0.52 mmol) and 4- methoxybenzyl amine (0.07 ml_, 0.80 mmol), in a similar manner as described above to give a white solid (0.03g, 19%).
  • ⁇ /-(2-Phenylethyl)-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 2,3,4,9-tetrahydro-1 H-carbazol-1 -one (0.1 g, 0.52 mmol) and phenethyl amine (0.10 mL, 0.80 mmol), in a similar manner as described above to give a white solid (0.04g, 23%).
  • Example 18 /V-IY 1 R)- 1 -Phenylethyl1-2.3,4.9-tetrahvdro-1 H-carbazol-1 -amine hydrochloride salt
  • N-[(1R)-1-Phenylethyl]-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 2,3,4,9-tetrahydro-1 H-carbazol-1 -one (0.1 g, 0.52 mmol) and (R)- ⁇ -methylbenzylamine (0.10 ml_, 0.80 mmol), in a similar manner as described above to give a mixture of diastereomers as a white solid (0.04g, 23%).
  • ⁇ /-Cyclohexyl-2,3,4,9-tetrahydro-1 /-/-carbazol-1 -amine hydrochloride salt was prepared from 2,3,4,9-tetrahydro-1 H-carbazol-1 -one (0.1 g, 0.52 mmol) and cyclohexyl amine (0.09 mL, 0.80 mmol), in a similar manner as described above to give a white solid (0.015g, 10%).
  • Example 20 ⁇ /-(2.3-Dihvdro-1 H-inden-2-yl)-2.3,4,9-tetrahvdro-1 H-carbazol-1 -amine hydrochloride salt
  • ⁇ /-Propyl-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 2,3,4,9-tetrahydro-1 H-carbazol-1 -one (0.1 g, 0.52 mmol) and ⁇ -propyl amine (0.065 mL, 0.80 mmol), in a similar manner as described above to give a white solid (0.060 g, 42%).
  • ⁇ /-(2-Methoxyethyl)-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 2,3,4,9-tetrahydro-i H-carbazol-1 -one (0.1 g, 0.52 mmol) and 2- methoxyethanamine (0.07 mL, 0.80 mmol), in a similar manner as described above to give a white solid (0.065 g, 43 %).
  • (2R)-2-Phenyl-2-(2,3 ,4,9-tetrahydro-1 H-carbazol-1 -ylamino)ethanol hydrochloride salt was prepared from 2,3,4,9-tetrahydro-i H-carbazol-1 -one (0.1 g, 0.52 mmol) and (2R)-2-amino-2-phenylethanol (0.11 mL, 0.80 mmol), in a similar manner as described above to give a white solid (0.01 g, 5%).
  • 6-Bromo- ⁇ /-(2-phenylethyl)-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 6-bromo-2,3,4,9-tetrahydro-1 H-carbazol-1 -one (0.1 g, 0.38 mmol) and phenethyl amine (0.10 ml_, 0.57 mmol), in a similar manner as described above to give a white solid (0.067 g, 44 %).
  • Example 27 (1 ffl-6-Bromo-/V-(2,3-dihvdro-1 H-inden-2-yl)-2,3,4.9-tetrahvdro-1 H- carbazol-1 -amine hydrochloride salt
  • Example 28 (1 S)-6-Bromo- ⁇ /-(2.3-dihvdro-1 H-inden-2-yl)-2.3.4.9-tetrahvdro-1 H- carbazol-1 -amine hydrochloride salt
  • ⁇ /-Benzyl-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1 -amine hydrochloride salt was prepared from 6-bromo-2,3,4,9-tetrahydro-1A7-carbazol-1-one (0.1 g, 0.38 mmol) and benzyl amine (0.062 mL, 0.57 mmol), in a similar manner as described above to give a white solid (0.042 g, 31%).
  • 6-Bromo- ⁇ /-[(1 R)-1 -phenylethyl]-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.1 g, 0.38 mmol) and (R)- ⁇ -methylbenzylamine (0.07 ml_, 0.57 mmol), in a similar manner as described above to give a white solid (0.08 g, 52%).
  • Example 31 A (1R)-6-bromo-/V-r(1R)-1-phenylethyl1-2 ⁇ 4,9-tetrahvdro-1/-/-carbazol- 1 -amine hydrochloride salt
  • Example 31 B Mf?)-6-bromo- ⁇ /-r(1ffl-1-phenylethvn-2.3.4,9-tetrahvdro-1H-carbazol- 1 -amine hydrochloride
  • 6-bromo- ⁇ /-(1 -methyl-1 -phenylethyl)-2,3,4,9-tetrahydro-1 /-/-carbazoI-1 -amine hydrochloride salt was prepared by dissolving 6-bromo-2,3,4,9-tetrahydro-7H- carbazol-1-ol (0.04 g, 0.15 mmol) in cumyl amine (0.5 ml_) in the presence of p- toluene sulfonic acid in a 2 ml_ reaction vessel with a stir bar. The vessel was sealed and heated in a Personal Chemistry Microwave Synthesizer for 10 min. at 15O 0 C.
  • 6-Bromo-/V-[(1 S)-1-phenylethyl]-2,3,4,9-tetrahydro-1/-/-carbazol-1 -amine hydrochloride salt was prepared in an identical manner as described above to give a white solid.
  • 6-Bromo- ⁇ /-methyl- ⁇ /-(2-phenylethyl)-2,3,4,9-tetrahydro-1/-/-carbazol-1-amine hydrochloride salt was prepared from 6-bromo-/V-(2-phenylethyl)-2,3,4,9-tetrahydro- 1 H-carbazol-1 -amine hydrochloride salt (0.05 g, 0.12 mmol), diisopropylethyl amine (0.04 ml_, 0.25 mmol) and methyl iodide (0.008 mL, 0.12 mmol) in THF (2.0 mL). The reagents were added to a round bottom flask and allowed to stir for 12 hrs.
  • Example 38 6-Bromo-9-methyl- ⁇ /-(2-phenylethvB-2,3 A9-tetrahvdro-1 /-/-carbazol-1 - amine hydrochloride salt
  • 6-Bromo-9-methyl- ⁇ /-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1 -amine hydrochloride salt was prepared by addition of methyl iodide (0.016 mL, 0.25 mmol) to a solution of 6-bromo-W-(2-phenylethyl)-2,3,4,9-tetrahydro-1 /-/-carbazol-1 -amine hydrochloride salt (0.05 g, 0.12 mmol) and sodium hydride (0.04 mL, 0.25 mmol) in THF (2.0 mL) that was under inert atmosphere and cooled to O 0 C. The mixture was allowed to warm to room temperature and stirred for 12 hrs.
  • 6-Bromo- ⁇ /-[(2R)-2-phenylpropyl]-2,3,4 ) 9-tetrahydro-1H-carba2 ⁇ l-1-amine hydrochloride salt was prepared from 6-bromo-2,3,4,9-tetrahydro-1/-/-carbazoI-1-one (0.1 g, 0.38 mmol) and (2/?)-2-phenylpropan-1 -amine (0.075 mL, 0.57 mmol), in a similar manner as described above to give a white solid (0.030 g, 19%).
  • 6-Methyl- ⁇ /-(2-phenylethyl)-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 6-methyl-2,3,4,9-tetrahydro-1 H-carbazol-1 -one (0.1 g, 0.5 mmol) and phenethyl amine (0.095 mL, 0.75 mmol), in a similar manner as described above to give a white solid (0.04 g, 23 %).
  • ⁇ /-(2,3-Dihydro-1 H-inden-2-yl)-6-methyl-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 6-methyl-2,3,4,9-tetrahydro-1/-/-carbazol-1-one (0.1 g, 0.5 mmol) and 2-indaneamine (0.10 mL, 0.75 mmol), in a similar manner as described above to give a white solid (0.027 g, 15 %).
  • 6-Methyl- ⁇ /-[(1 f?)-1 -phenylethyl]-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 6-methyl-2,3,4,9-tetrahydro-1 H-carbazol-1 -one (0.1 g, 0.5 mmol) and (R)- ⁇ -methylbenzy ⁇ amine (0.07 mL, 0.75 mmol), in a similar manner as described above to give a white solid (0.075 g, 44%).
  • 6-Methyl- ⁇ /-[(1S)-1-phenylethyl]-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 6-methyl-2,3,4,9 ⁇ tetrahydro-1 H-carbazol-1 -one (0.1 g, 0.5 mmol) and S- ⁇ -methylbenzylamine in an identical manner as above.
  • ⁇ /-Benzyl-6-nitrd-2,3,4,9-tetrahydro-1/-/-carbazol-1 -amine hydrochloride salt was prepared from 6-nitro-2,3,4,9-tetrahydro-1/-/-carbazol-1-one (0.1 g, 0.22 mmol) (see, J. Heterocyclic Chemistry, 1990, 27(7), 1947-51 , herein incorporated by reference with regard to the synthesis of this starting material) and benzyl amine (0.03 mL, 0.33 mmol), in a similar manner as described above to give a white solid (0.01 g, 8%).
  • 6-Nitro- ⁇ /-[(1 R)- 1 -phenylethyl]-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride salt was prepared from 6-bromo-2,3,4,9-tetrahydro-1 H-carbazol-1 -one (0.05 g, 0.22 mmol) and (R)- ⁇ -methylbenzylamine (0.04 mL, 0.33 mmol), in a similar manner as described above to give a white solid (0.005 g, 6%).
  • Example 50 7-Bromo- ⁇ /-(2-phenylethyl)-1 ,2,3,4-tetrahydrocvclopenta[ib1indol-3- amine hydrochloride salt
  • ⁇ /-Benzyl-6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-1 -amine hydrochloride salt was prepared from 6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-1 -amine (0.05 g, 0.23 mmol), benzaldehyde (0.04 mL, 0.35 mmol) in THF in a similar manner as described above to give a white solid (0.02 g, 25%).
  • Example 54 ⁇ /-Benzyl-2-bromo-5,6,7,8,9, 10-hexahvdrocycloheptarfelindol-6-amine hydrochloride
  • the amine was diluted with diethyl ether and HCI (1.0 M in diethyl ether) was added. The solution was concentrated, dissolved in acetonitrile and water and lyophilized to give 25mg (38%). of a light brown solid.
  • 6-Bromo- ⁇ /-(4-fluorobenzyl)-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine hydrochloride was prepared from 6-bromo-2,3,4,9-tetrahydro-1 H-carbazol-1 -one (100 mg, 0.38 mmol) and 4-fluorobenzylamine (70 mg, 0.57 mmol) in a similar manner as described above to give 30 mg (19%).
  • Example 59 ⁇ /-r(1ffl-1 -Phenylethyll-6-(trifluoromethyl)-2.3.4,9-tetrahvdro-1 H- carbazol-1 -amine hydrochloride
  • 6-Bromo-9-(phenylsulfonyl)-2,3,4,9-tetrahydro-1/-/-carbozol-1-one To a solution of 6- bromo ⁇ SA ⁇ -tetrahydro-IH-carbazoM-one (300 mg, 1.1 mmol) in methylene chloride (10 mL) was added benzene sulfonylchloride (201 mg, 1.1 mmol), aqueous sodium hydroxide (5N, 1.1 mL, 5.5 mmol) and benzyltriethylammonium chloride (catalytic). The reaction mixture was stirred overnight at room temperature.
  • 6-Bromo-9-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-1-ol To a solution of 6- bromo-9-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbozol-1-one (150 mg, 0.37 mmol) in methanol (10 mL) was added sodium borohydride (30 mg, 0.79 mmol). The reaction was stirred for 30 min at room temperature and quenched with water (10 mL).
  • 6-Bromo-1 -[(phenyImethyl)oxy]-2,3,4,9-tetrahydro-1 H-carbazole To a solution of 6- bromo-9-(phenylsulfonyl)-2,3,4,9-tetrahydro-1/-/-carbazol-1-ol (25 mg, 0.06 mmol) in N,N-dimethylformamide (2 mL) was added benzyl bromide (0.5 mL) and sodium hydride (60% in oil, 50 mg, 1.2 mmol). The reaction was stirred 10 min and quenched with water (1 mL).
  • Example 65 ⁇ /-(6-Bromo-2,3,4.9-tetrahvdro-1 /-/-carbazol-1 -yl)-/V-isopropylurea
  • ⁇ /-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)- ⁇ / l -isopropylurea was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1 -amine and isopropyl isocyanate to give a tan solid (58% yield).
  • ⁇ /-(6-Bromo-2,3,4,9-tetrahydro-1 H-carbazol-1 -yl)acetamide was prepared from 6- bromo-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine and acetyl chloride in the presence of diisopropylethylamine to give a tan solid (52% yield).
  • ⁇ /-(6-Bromo-2,3,4,9-tetrahydro-1 H-carbazol-1 -yljcyclohexanecarboxamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine and cyclohexane carbonyl chloride to give a tan solid (62% yield).
  • ⁇ /-(6-Bromo-2,3,4,9-tetrahydro-1 H-carbazol-1 -yl)methanesulfonamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1 H-carbazol-1 -amine and methane sulfonyl chloride to give a tan solid (57% yield).
  • Compounds of the current invention are believed useful in the treatment and/or prophylaxis of conditions and diseases associated with HcV infection.
  • Activity mediated through HCV was determined using an ET replicon line.
  • the Materials used include a Medium comprised of DMEM (1X liquid, high glucose); Invitrogen cat# 11965-092; 100 x Penicillin/Streptomycin solution (10, 000 Units/mL); Invitrogen cat# 15140-122; 100 x Non-essential amino acid solution (10 mM); Invitrogen cat# 11140-050; Fetal bovine serum; JRH Biosciences cat# 12107- 500M; Geneticin (50 mg/mL); Invitrogen cat# 10131-035
  • the Luciferase assay reagents include Steady-Glo Luciferase assay system, cat# E2550 (Promega)
  • the ET replicon line (see Lohmann et al. (1999), Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285: 110-113; Krieger et al. (2001), Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations. J. Virol. 75: 4614-4624; and Vrolijk et al. (2003), A replicon-based bioassay for the measurement of interferons in patients with chronic hepatitis C. J. Virol. Meth.
  • the ET replicon line includes Huh7 cells stably transfected with HCV genotype 1 b strain Con1 replicon.
  • This replicon expresses the firefly luciferase, has the coding region for ubiquitin inserted upstream of the neomycin gene, and carries three cell culture- adaptive mutations that enhance RNA replication cooperatively (E1202G, T1280I, and S2197P).
  • the ET cell line was obtained under licence from: ReBLikon GmbH, Nach dem alternative Schloss 22, 55239 Gau-Odemheim, Germany.
  • Cells are maintained at 37°C, 5% CO 2 , in DMEM with 10% FCS, 1 x penicillin/streptomycin, 1 x non-essential amino acids, 0.5 mg/mL Geneticin. For passage, cells are washed once with PBS, and incubated at 37 0 C with sufficient trypsin (0.05%) / versene to cover the monolayer. Once detached from the flask, cells are mixed with several mLs of DMEM + 10% FBS to inactivate the trypsin, then diluted appropriately (usually 1 in 5 or 1 in 10) with sufficient medium to pass to a new flask. For a T225 flask, 40-50 mLs total volume of cells + medium is typically used. To prevent the density dependent drop in replicon RNA, the ET cell line is maintained at sub-confluent (60-80%) levels.
  • Compounds are diluted in DMSO across the first 10 wells of a Costar V- bottom 96-well plate using a Biomek 2000 Workstation (Beckman-Coulter), with 0.5 log 10 dilution intervals. DMSO only is added to the last two columns of the plate. The top concentration of drug in this master plate is typically 2.5 mM. A 1/5 dilution of the compounds is made by adding DMEM + 10% FBS with a multichannel pipettor, giving a top concentration of 500 ⁇ M. 5 ⁇ L of diluted compounds is transferred into black Costar flat bottom 96-well daughter plates using a RapidPlate workstation (Zymark).
  • Cells are grown to approximately 80% confluency and trypsinised as described above. Cells are counted in a Levy Hemocytometer and diluted to 20,000 cells/ml in DMEM containing 10% FBS, 1 x penicillin/streptomycin, 1x NEAAs. (Note: Geneticin is omitted for the assay).
  • Steady-Glo reagent is prepared according to the manufacturer's instructions, by mixing the Steady-Glo Buffer and Steady-Glo substrate Buffer at room temperature. Medium is removed from the 96-well plates containing ET cells treated with compound using a multi-channel aspirator. 100 ⁇ l of Steady-Glo reagent is added to each well using a multichannel pipettor or Multidrop dispensor. Plates are incubated at room temperature for 5 minutes to ensure complete lysis, and mixed by gentle shaking.
  • Luciferase activity is read using a Topcount (PE Biosystems), with a 1 -second read-time per well. Data are analyzed and IC 50 curves generated using RoboFit software.
  • Test compounds were employed in free or salt form.

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Abstract

Cette invention concerne des composés qui sont utiles dans le traitement des virus appartenant à la famille des Flaviviridae, y compris les flavivirus, les pestivirus, et les virus de l'hépatite C. Cette invention concerne également des composés utiles dans le traitement ou la prophylaxie de la dengue bovine, de la fièvre jaune, des infections par le virus du Nil occidental et des infections par le virus de l'hépatite C.
EP05857834A 2004-11-22 2005-11-14 Inhibiteurs du virus de l'hepatite c Withdrawn EP1817026A2 (fr)

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US20090170906A1 (en) * 2004-11-22 2009-07-02 Kristjan Gudmundsson Hcv inhibitors
UA98777C2 (en) * 2006-11-20 2012-06-25 Эли Лилли Энд Компани Tetrahydrocyclopenta[b]indole compounds as androgen receptor modulators
MX2009008439A (es) * 2007-02-12 2009-08-13 Intermune Inc Nuevos inhibidores de la replicacion del virus de hepatitis c.
WO2008131197A1 (fr) 2007-04-19 2008-10-30 Smith & Nephew, Inc. Polymères à mémoire de forme multimodaux
WO2009054401A1 (fr) * 2007-10-26 2009-04-30 Kagoshima University Agent anti-viral contenant un composé aromatique hétérocyclique en tant qu'ingrédient actif
WO2009103022A1 (fr) * 2008-02-13 2009-08-20 Itherx Pharmaceuticals, Inc. Dérivés de cycloindoles à cycle condensé substitué et leurs procédés d’utilisation
JP6653573B2 (ja) 2012-05-22 2020-02-26 トラスティーズ・オブ・ダートマウス・カレッジ シクロアルカニル［ｂ］インドール、シクロアルカニル［ｂ］ベンゾフラン、シクロアルカニル［ｂ］ベンゾチオフェンを合成するための方法、化合物および使用の方法
WO2014041125A1 (fr) * 2012-09-13 2014-03-20 Baden-Württemberg Stiftung Gmbh Inhibiteurs spécifiques de la protéine p21 comme agents thérapeutiques
CN104774208A (zh) * 2015-04-24 2015-07-15 南京靖龙药物研发有限公司 一种氘标记吡吲哚盐酸盐的制备方法
US20200147069A1 (en) * 2017-06-19 2020-05-14 The Board Of Trustees Of The Leland Stanford Junior University Compounds for The Reduction of The Deleterious Activity of Extended Nucleotide Repeat Containing Genes
US10882821B1 (en) 2017-09-26 2021-01-05 The Board Of Trustees Of The Leland Stanford Junior University Enantiomeric compound for the reduction of the deleterious activity of extended nucleotide repeat containing genes
WO2020131573A1 (fr) * 2018-12-18 2020-06-25 Nuredis, Inc. Composés pour la réduction de l'activité délétère de gènes contenant une répétition de nucléotides étendue

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US20030139609A1 (en) * 2001-09-10 2003-07-24 Skibo Edward B. Aziridinyl quinone antitumor agents based on indoles and cyclopent[b]indoles
EP1440068A1 (fr) * 2001-11-02 2004-07-28 Glaxo Group Limited Derives d'acyl-dihydro-pyrrole utilises comme inhibiteurs du vhc
AU2003287160A1 (en) * 2002-10-15 2004-05-04 Rigel Pharmaceuticals, Inc. Substituted indoles and their use as hcv inhibitors
DE602004019541D1 (de) * 2003-08-26 2009-04-02 Smithkline Beecham Corp Cycloalkyläbü kondensierte indole
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